盐酸三环哌酯在大鼠体内外的代谢

用大鼠原位灌流肝脏、整体实验和大鼠肝脏微粒体酶制备对盐酸三环哌酯(TCPN)的代谢转化进行了研究。结果经大鼠原位肝脏灌流后,灌流液经提取和HPLC分离制备,得到两个代谢产物。经MS,NMR,IR和UV鉴定,证明产物I是TCPN氮上脱甲基的产物,产物I是TCPN苯环羟化的产物。从大鼠igTCPN后的尿中及在TCPN和肝脏微粒体的温孵液中均得到产物I和产物II,提示TCPN的代谢转化主要由大鼠肝脏微粒体酶催化。以³H]QNB为配体对TCPN及其代谢产物的受体结合活性进行了研究,结果表明产物I和产物I与M受体的亲和力分别是TCPN的1/20和1/50。

IN VIVO AND IN VITRO METABOLISM OF TRICYCLOPINATE HYDROCHLORIDE IN THE RAT

The metabolism of tricyclopinate hydrochloride(TCPN), a new anticholinergic agent, was studied by in situ perfused rat liver preparation. Two metabolites were isolated by HPLC. Metabolite I was identified as an N demethylation product, while metabolite II was shown to be an arylhydroxylation product. Metabolite I and metabolite II were also isolated from the urine of the rat given TCPN ig. This result shows that the two metabolites from the perfused rat liver are just the final metabolites produced in vivo . The metabolites in rat liver microsomes were also identified as those just described. These results suggest that the biotransformation reaction of TCPN is mainly catalyzed by the enzyme in rat liver microsomes. The results of experiment on receptor activity indicate that the action potency with mAChR of metabolite I and metabolite II was only 1/20 and 1/50, respectively, of that of TCPN.